OSU-A9 inhibits angiogenesis in human umbilical vein endothelial cells via disrupting Akt-NF-κB and MAPK signaling pathways

Hany A. Omar, El Shaimaa A Arafa, Samir A. Salama, Hany H. Arab, Chieh Hsi Wu, Jing Ru Weng

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

Since the introduction of angiogenesis as a useful target for cancer therapy, few agents have been approved for clinical use due to the rapid development of resistance. This problem can be minimized by simultaneous targeting of multiple angiogenesis signaling pathways, a potential strategy in cancer management known as polypharmacology. The current study aimed at exploring the anti-angiogenic activity of OSU-A9, an indole-3-carbinol-derived pleotropic agent that targets mainly Akt-nuclear factor-kappa B (NF-κB) signaling which regulates many key players of angiogenesis such as vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMPs). Human umbilical vein endothelial cells (HUVECs) were used to study the in vitro anti-angiogenic effect of OSU-A9 on several key steps of angiogenesis. Results showed that OSU-A9 effectively inhibited cell proliferation and induced apoptosis and cell cycle arrest in HUVECs. Besides, OSU-A9 inhibited angiogenesis as evidenced by abrogation of migration/invasion and Matrigel tube formation in HUVECs and attenuation of the in vivo neovascularization in the chicken chorioallantoic membrane assay. Mechanistically, Western blot, RT-PCR and ELISA analyses showed the ability of OSU-A9 to inhibit MMP-2 production and VEGF expression induced by hypoxia or phorbol-12-myristyl-13-acetate. Furthermore, dual inhibition of Akt-NF-κB and mitogen-activated protein kinase (MAPK) signaling, the key regulators of angiogenesis, was observed. Together, the current study highlights evidences for the promising anti-angiogenic activity of OSU-A9, at least in part through the inhibition of Akt-NF-κB and MAPK signaling and their consequent inhibition of VEGF and MMP-2. These findings support OSU-A9's clinical promise as a component of anticancer therapy.

Original languageEnglish
Pages (from-to)616-624
Number of pages9
JournalToxicology and Applied Pharmacology
Volume272
Issue number3
DOIs
Publication statusPublished - Nov 1 2013
Externally publishedYes

Fingerprint

NF-kappa B
Endothelial cells
Human Umbilical Vein Endothelial Cells
Mitogen-Activated Protein Kinases
Vascular Endothelial Growth Factor A
Matrix Metalloproteinase 2
Polypharmacology
Chorioallantoic Membrane
Cell Cycle Checkpoints
Matrix Metalloproteinases
Chickens
Neoplasms
Cell proliferation
Acetates
Western Blotting
Enzyme-Linked Immunosorbent Assay
Cell Proliferation
Apoptosis
Assays
Polymerase Chain Reaction

Keywords

  • Akt-NF-κB
  • Angiogenesis
  • MAPKs
  • MMP-2
  • OSU-A9
  • VEGF

ASJC Scopus subject areas

  • Pharmacology
  • Toxicology

Cite this

OSU-A9 inhibits angiogenesis in human umbilical vein endothelial cells via disrupting Akt-NF-κB and MAPK signaling pathways. / Omar, Hany A.; Arafa, El Shaimaa A; Salama, Samir A.; Arab, Hany H.; Wu, Chieh Hsi; Weng, Jing Ru.

In: Toxicology and Applied Pharmacology, Vol. 272, No. 3, 01.11.2013, p. 616-624.

Research output: Contribution to journalArticle

Omar, Hany A. ; Arafa, El Shaimaa A ; Salama, Samir A. ; Arab, Hany H. ; Wu, Chieh Hsi ; Weng, Jing Ru. / OSU-A9 inhibits angiogenesis in human umbilical vein endothelial cells via disrupting Akt-NF-κB and MAPK signaling pathways. In: Toxicology and Applied Pharmacology. 2013 ; Vol. 272, No. 3. pp. 616-624.
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AU - Wu, Chieh Hsi

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